Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

abstract: ...There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis -acting variants represent an important source of phenotypic variation. Consequently, c is -regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10 -6 ). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ , encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS) , encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ ( P = 8.28x10 -14 ), MRPS18C ( P = 1.94x10 -27 ) and FAM175A ( P = 3.83x10 -3 ), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

... receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10 -6 ). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ , encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS) , encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ ( P = 8.28x10 -14 ), MRPS18C ( P = 1.94x10 -27 ) and FAM175A ( P = 3.83x10 -3 ), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. breast cancer genetic susceptibility association studies differential allelic expression cis-regulatory variants INTRODUCTION Breast cancer is a complex disease with a strong

... BRCA2 carriers. However, none of the SNPs showed associations with breast cancer risk, including rs11099601, which had a P -value of 0.89 and 0.78 in BRCA1 and BRCA2 carriers respectively. rs11099601 lies on 4q21 in a region containing numerous genes including FAM175A ( ABRAXAS) , HELQ and MRPS18C . It was selected on the basis of its association with differential allelic expression in FAM175A (see S2 Figure ). In order to further map the novel association at this locus, we imputed genotype data for

... histone mark associated with active promoters, and our candidate variant, rs11099601 in breast myoepithelial cells. Further analysis of other genotyped and imputed variants correlated with rs11099601, revealed that only rs6844460 ( P = 4.2x10 -6 , r 2 = 0.967) overlapped with several chromatin biofeatures in mammary cells. rs6844460, which is located within intron 1 of FAM175A , overlapped with a DNase hypersensitivity site in MCF-7 cells, with H3K4me3 histone marks (associated with active promoters

... mammary cell super-enhancer locations as defined in Hnisz et al. are shown in HMEC cells. Predicted enhancer-promoter determined interactions in MCF7 and HMEC cells, as defined by the integrated method for predicting enhancer targets (IM-PET) are shown. D. RNA-Seq data from MCF7 and HMEC cell lines. The value of the RNA-Seq analysis corresponds to the mean RPM value for FAM175A , MRPS18C , HELQ , AGPAT9 , HSPE and COQ2 from four HMEC and 19 MCF7 datasets, respectively. The annotation was obtained

... encompassing rs11099601, in the vicinity of the promoter regions of HELQ, MRPS18C and FAM175A genes. ChiA-PET data for CTCF in MCF-7 cells showed fewer interactions, none of which encompassed variant rs11099601. Similarly Hi-C data revealed few interactions in HMEC cells, none of which included our top candidate SNP (Figure 2B ). Lastly, although super-enhancers mapped to the 4q21 locus in HMEC mammary cells, none overlapped with our top candidate SNPs (Figure 2C ). Predicted enhancer-promoter interactions

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Gene: FAM175A - family with sequence similarity 175, member A - (NCBI)

Protein : 4jlu

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